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Gregg W. Stone MD for the ACUITY Investigators

Prospective, Randomized Comparison of Routine Upfront Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: The ACUITY Timing Trial. Gregg W. Stone MD for the ACUITY Investigators. Disclosure. Gregg W. Stone

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Gregg W. Stone MD for the ACUITY Investigators

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  1. Prospective, Randomized Comparison of Routine Upfront Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: The ACUITY Timing Trial Gregg W. Stone MD for the ACUITY Investigators

  2. Disclosure • Gregg W. Stone Consultant to The Medicines Company

  3. Background I • Optimal management of ACS1,2 consists of an early invasive strategy for moderate-high risk pts, followed by revascularization with PCI or CABG • Median time to cath 21 hours3 • 55% PCI, 12% CABG, 33% medical mgt3 • GP IIb/IIIa inhibitors are a class I indication1,2 (and are used in 80% of pts during PCI of ACS3) • Guidelines recommend that they be administered either upstream in all pts (PRISM PLUS and PURSUIT), or their use may be deferred for selective administration in the cath lab only for PCI 1 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; 3www.crusade.org

  4. Background II • However, the combination of invasive procedures with GP IIb/IIIa inhibitors, aspirin, clopidogrel, and antithrombin medications results in a high rate of hemorrhagic complications • The upstream use of GP IIb/IIIa inhibitors in all patients may further increase bleeding • Whether upstream GP IIb/IIIa use reduces ischemic complications sufficiently to justify such an increase is unknown

  5. The Question to Answer • When seeing a patient in the emergency department with moderate-high risk ACS in whom an invasive strategy is planned: • Should GP IIb/IIIa inhibitors be started immediately? Or • Should their use be withheld to • First perform coronary arteriography • And then only start GP IIb/IIIa inhibition if PCI is performed?

  6. Optimal Timing of GPI in ACS: Hypotheses • In moderate-high risk patients with ACS undergoing an invasive strategy, compared to the routine upstream use of GP IIb/IIIa inhibitors in all patients, withholding upfront GP IIb/IIIa use for deferred administration in the cath lab only to patients undergoing PCI will result in: • Similar 30 day rates of death, MI or unplanned revascularization for ischemia • Reduced rates of major bleeding complications • Improved cost-effectiveness

  7. Medical management UFH or Enoxaparin + GP IIb/IIIa PCI Bivalirudin + GP IIb/IIIa Angiography within 72h R* Bivalirudin Alone CABG Study Design – First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  8. UFH or Enoxaparin Routine upstream GPI in all pts Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Routine upstream GPI in all pts Deferred GPI for PCI only R R GPI started in CCL for PCI only Bivalirudin Alone Secondary analysis Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) UFH, Enoxaparin, or Bivalirudin VS. Moderate- high risk ACS Primary analysis Aspirin in all Clopidogrel dosing and timing per local practice ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  9. Major Entry Criteria Moderate-high risk unstable angina or NSTEMI Inclusion Criteria Exclusion Criteria • Age ≥18 years • Chest pain ≥10’ within 24h • At least one of: • New ST depression or transient ST elevation ≥1 mm • Troponin I, T, or CKMB • Documented CAD • All other 4 TIMI risk criteria • Age ≥65 years • Aspirin within 7 days • ≥2 angina episodes w/i 24h • ≥3 cardiac risk factors • Written informed consent • No angiography within 72h • Acute STEMI or shock • Bleeding diathesis or major bleed within 2 weeks • Platelet count ≤100,000/mm3 • INR >1.5 control • CrCl ≤30 ml/min • ≥2 prior LMWH doses • Any prior abciximab • Prior tirofiban or eptifibatide if unable to be d/c for 4 hrs • Allergy to drugs, contrast ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  10. 3 Primary Endpoints (at 30 days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding • Death from any cause • Myocardial infarction - During medical Rx: Any biomarker elevation >ULN - Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves - Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves • Unplanned revascularization for ischemia

  11. 3 Primary Endpoints (at 30 days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding • Non CABG related bleeding • - Intracranial bleeding or intraocular bleeding • -Retroperitoneal bleeding • -Access site bleed requiring intervention/surgery • -Hematoma ≥5 cm • -Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source • -Blood product transfusion • Reoperation for bleeding

  12. Power analysis and statistics Routine upstream GP IIb/IIIa inhibition (n=4,600) vs. deferred GP IIb/IIIa inhibition in the CCL for PCI only (n=4,600) • The trial was powered to demonstrate non-inferiority for the composite ischemic endpoint at 30 days between the 2 groups (treatment strategy) • 1-sided upper bound of the confidence interval of the observed difference was used for non-inferiority ( = 0.025, =25%) • 2-sided confidence intervals used for superiority testing ( = 0.05)

  13. (4) Norway Sweden (6) (5) Denmark Finland (3) (4) Netherlands Canada (26) (5) Belgium Poland (1) (12) UK Germany (66) (8) France USA (246) Austria (4) Italy (15) (25) Spain (4) New Zealand (17) Australia ACUITY Enrollment 13,819 pts randomized at 448 centers in 17 countries

  14. 89 (0.6%) Norway Sweden 175 (1.3%) 150 (1.1%) Denmark Finland 51 (0.4%) 132 (1.0%) Netherlands 438 (3.2%) Canada 198 (1.4%) Belgium Poland 14 (0.1%) 162 (1.2%)UK Germany 2561 (18.5%) 155 (1.1%)France 7851 (56.8%) USA Austria 356 (2.6%) Italy 238 (1.7%) 547 (4.0%)Spain 203 (1.5%)New Zealand 499 (3.6%)Australia ACUITY Enrollment 13,819 pts randomized at 448 centers in 17 countries

  15. UFH or Enoxaparin Routine upstream GPI in all pts (4,605) Routine upstream GPI in all pts GPI started in CCL for PCI only Bivalirudin Routine upstream GPI in all pts Deferred GPI for PCI only (n=4,602) R R GPI started in CCL for PCI only Bivalirudin Alone (n=4,612) Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) UFH, Enoxaparin, or Bivalirudin VS. Moderate- high risk ACS (n=13,819) Aspirin in all Clopidogrel dosing and timing per local practice ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

  16. Baseline Characteristics

  17. Baseline High Risk Features

  18. Invasive Management

  19. Study Medications: GP IIb/IIIa Inhibitors *In PCI pts only; †In a few patients the timing onset was not known

  20. Use During PCI (%) Routine Upstream GP IIb/IIIa Deferred PCI GP IIb/IIIa 1.1 33.5 33.4 4.5 65.4 62.1 N=2,559 N=2,405 GP IIb/IIIa Selection Initiated Pre Angio (%) Routine Upstream GP IIb/IIIa Deferred PCI GP IIb/IIIa 0.4 7.6 43.8 34.4 65.2 48.6 N=4,339 N=212 Abciximab ■ Eptifibatide ■ Tirofiban ■

  21. Primary Endpoint Measures Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa PNI <0.0001 PSup = 0.93 PNI = 0.044 PSup = 0.13 PNI < 0.0001 PSup = 0.009

  22. Primary Endpoint Measures (ITT) Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa p value(non inferior)(superior) Deferred IIb/IIIa Primary endpoint Risk ratio ±95% CI Upstream IIb/IIIa RR (95% CI) <0.001 0.93 Net clinical outcome 11.7% 11.7% 1.00 (0.89-1.11) Ischemic composite 0.06 0.13 Upper boundary non-inferiority 7.1% 7.9% 1.12 (0.97-1.29) <0.001 0.01 Major bleeding 6.1% 4.9% 0.80 (0.67-0.95) Deferred PCI GPI better Routine Upstream GPI better

  23. Components of the Ischemic Composite Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa PSup = 0.13 PSup = 0.48 PSup = 0.70 PSup = 0.03

  24. P (log rank) = 0.14 Ischemic Composite Endpoint Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa 15 Estimate Routine Upstream IIb/IIIa (N=4605) 7.1% Deferred PCI IIb/IIIa (n=4602) 7.9% 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization

  25. Major Bleeding (Primary Endpoint)

  26. Bleeding Endpoints (Non-CABG)

  27. Upstream IIb/IIIa Deferred IIb/IIIa 14.5% 13.7% 15.8% 18.5% 5.5% 5.8% 9.5% 8.0% 13.5% 15.3% 3.3% 2.4% 6.5% 7.8% 3.3% 4.5% 2.6% 3.7% Actual Management Routine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIa Risk ratio ±95% CI RR (95% CI) P Pint Net Clinical Outcome PCI (n=5170) CABG (n=1048) Medical (n=2989) 1.06 (0.93-1.22) 0.38 0.25 0.34 0.85 (0.65-1.12) 0.96 (0.72-1.29) 0.80 Composite Ischemic PCI (n=5170) CABG (n=1048) Medical (n=2989) 1.19 (1.00-1.42) 0.05 0.39 0.15 0.88 (0.65-1.18) 1.39 (0.91-2.12) 0.13 Major Bleeding PCI (n=5170) CABG (n=1048) Medical (n=2989) 0.84 (0.69-1.02) 0.08 0.33 0.74 0.74 (0.40-1.34) 0.70 (0.47-1.05) 0.09 Deferred PCI GPI better Routine Upstream GPI better

  28. Primary Endpoint Measures - Timing Analysis Duration from Initiation of GP IIb/IIIa to Angio/Interv Upstream GPI group (N=4,342)

  29. Composite Ischemic - Timing Analysis Randomization to Angio/Intervention within Index Hospitalization P = 0.06 P = 0.08 P = 0.60 Short(<3.0hrs) Medium(3.0-19.7 hrs) Long(>19.7 hrs) Median: 1.5 hrs 6.1 hrs 30.0 hrs

  30. 11.7% 11.7% PNI <0.0001 PNI = 0.044* PSup = 0.13 7.1% 7.9% 6.1% 4.9% PSup = 0.009 Summary ConclusionsACUITY Timing Trial Routine upstream GPI in all pts Deferred GPI for PCI only Net Composite Outcome Ischemic Composite Major Bleeding *RR [95%CI] = 1.12 [0.97-1.29]

  31. Net Clinical Outcome Composite Endpoint Upstream IIb/IIIa vs. Deferred IIb/IIIa vs. Bivalirudin alone 15 10 Cumulative Events (%) Estimate P (log rank) 5 11.7% Routine Upstream IIb/IIIa (N=4605) 0.88 11.7% Deferred PCI IIb/IIIa (n=4602) 0.009 10.1% Bivalirudin alone (N=4612) 0 0 5 10 15 20 25 30 35 Days from Randomization

  32. Ischemic Composite Endpoint Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone 15 Estimate P (log rank) 7.1% Routine Upstream IIb/IIIa (N=4605) 0.14 7.9% Deferred PCI IIb/IIIa (n=4602) 0.28 10 7.8% Bivalirudin alone (N=4612) Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization

  33. 15 10 5 0 0 5 10 15 20 25 30 35 Major Bleeding Endpoint Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone Estimate P (log rank) 6.1% Routine Upstream IIb/IIIa (N=4605) 0.009 4.9% Deferred PCI IIb/IIIa (n=4602) <0.001 3.0% Bivalirudin alone (N=4612) Cumulative Events (%) Days from Randomization

  34. Clinical Implications • In pts with moderate-high risk ACS undergoing an early invasive strategy, compared to the routine upstream use of GP IIb/IIIa inhibitors in all pts, withholding upfront IIb/IIIa inhibitor use for selective initiation in the cath lab only to pts undergoing PCI results in: • Similar rates of adverse ischemic events, though a slight increase cannot be excluded • Reduced rates of major and minor bleeding

  35. Clinical Implications • The implications of these results will be further examined through detailed angiographic analysis, long-term clinical follow-up (to 1-year) and formal cost-effectiveness analysis • Regardless, in the context of the entire ACUITY trial, both upstream and selective GP IIb/IIIa inhibitor strategies (with either UFH, enoxaparin or bivalirudin) provided inferior net clinical outcomes compared to use of bivalirudin alone

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